Pathogenesis of Hidradenitis Suppurativa: An Immunological Perspective

Hidradenitis suppurativa, HS (syn: acne inversa) is a cicatrizing, aberrantly keratinizing, follicular-occlusive systemic inflammatory disorder predominantly affecting (pilosebaceous units of apocrine gland rich) intertriginous areas of the body which have hypoxic, hyperthermic, and moist environment/background.[1] It has recently been recognized as a chronic immune-mediated auto-inflammatory keratinizing disease.[2,3] It shows a chronic relapsing-remitting course, mixed and profound inflammation with localized destructive skin alterations leading to the development of painful nodules, difficult-to-heal abscesses, and pus-discharging foul-smelling sinuses and tracts. HS has a significant impact on the patient's quality of life with distressing social, working, and psychological aspects. It poses significant therapeutic challenges for clinicians with most patients responding only partially, with subsequent therapeutic escape and recurrences.[4]

The underlying pathogenic mechanisms of this chronic debilitating disease are complex and heterogeneous and are, as yet, incompletely understood.[5] A dynamic interplay of the individual's genetic landscape, tissue-specific immune micro-environment, host-microbial interactions, metabolic stressors, and associated risk factors and co-morbidities have been implicated in the pathophysiology of this multi-factorial disease.[6] The immunopathogenesis of HS represents a complex and poorly delineated interaction of the neutrophil-dominant, an inflammasome-driven innate component of the immune system, T helper (Th) 1 and Th17 (but not Th22) cells of the adaptive immune system, as well as non-immune cells including fibroblasts, keratinocytes, and endothelial cells, leading to the production of enormous amounts of pro-inflammatory cytokines (along with a significant anti-inflammatory interleukin (IL)-10 mediated element) that, in turn, create, sustain, and amplify numerous reverberating immunological circuits.[7]

Genetic Factors

Heterozygous loss-of-function mutations in genes encoding for components of the γ-secretase complex (an intramembrane protease that cleaves various substrates including Notch) with their attendant haploinsufficiency results in impaired Notch signaling. γ-secretase, by regulated intramembrane proteolysis of Notch, is responsible for regulating Notch-mediated highly-conserved cell signaling involved in skin and hair follicle stem cell homeostasis via growth arrest and cell terminal differentiation. Reduced Notch signaling results in perturbations of sebaceous gland differentiation and terminal differentiation of the epidermis leading to enhanced epidermal/epithelial fragility, finally contributing to the development of epidermal tracts, sinuses, and comedones, characteristic features of HS.[8]

The traditional pathologic model describes HS pathophysiology initiating with follicular occlusion/plugging/dilatation of the follicular-pilosebaceous unit (as a primary event) resulting from inflammation-driven infundibular hyperkeratosis, acanthosis, and perifolliculitis that is worsened by impaired Notch signaling and smoking. This is followed by a follicular rupture with spillage of intrafollicular contents (cell-damage associated molecules and bacteria) inciting innate immune responses, seen histologically as a neutrophil-rich reaction further ensuring a continued influx of macrophages and other immune cells [Figure 1].

Figure 1.

Flow chart summarizing sequence of events in HS

Lifestyle Factors

Lifestyle factors including smoking (favoring inflammasome activation, infundibular acanthosis, and dysbiosis), high-fat diet (causing gut dysbiosis and dysregulation of the 1-carbon metabolism), and central obesity (inducing mechanical stress with resultant epidermal micro injuries, maceration, chronic low-grade inflammation, increased pro-atherogenic/insulin resistance-promoting adipokine pattern), all contribute to the development of HS.[7] The role of sex hormones has also been implicated, as suggested by androgen receptor pathway activation leading to increased local macrophage TNF-α production. Genetic and epigenetic factors have also been incriminated in enhancing androgen responsiveness on a post-receptor basis.[9]

Co-morbidities

Inflammation in patients with HS is not restricted to the skin but is systemic as demonstrated by the co-existence of HS with several co-morbid immune-mediated inflammatory diseases, notably inflammatory bowel disease; metabolic syndrome, and a plethora of cardio-metabolic pathologies including insulin resistance, hyperglycemia, type 2 diabetes mellitus, hypertension, and lipid abnormalities (aggravated by the paucity of IL-22 cells).[7] Pilonidal sinuses, pilonidal cysts, and dissecting cellulitis, other disorders characterized by follicular occlusion, also have a very strong associations with HS.

Microbiome

Altered cutaneous microbial metabolism and landscape, perpetuated by dysregulated antimicrobial peptides (AMPs) particularly dermcidin, and architectural disruptions in the skin and its adnexa lead to loss of skin commensals with the growth of Gram-negative anaerobes such as Prevotella and Porphyromonas in chronic suppurating sinus tracts and fistulas of moderate to severe HS, encouraging bacterial biofilm formation (augmented by smoking) with attendant propagation of chronic inflammation.[10]

Innate immunity

Recently there has been a paradigmatic shift from follicular-occlusion focussed understanding to a greater appreciation of the role of auto-inflammatory mechanisms in HS pathogenesis.[11] Autoinflammatory etiological frameworks are underpinned by a massive involvement of innate immunity involving both structural and cellular innate immune sensors.[12] Upregulation of IL-1β signifies an important autoinflammatory component in the pathogenesis of this disease. Dysregulated Toll-like receptor (TLR) signaling (potentiated by defective Notch signaling), inappropriate AMP production, abnormal systemic complement activation (anaphylatoxins C5a and C5b-9), upregulated type I interferon (INF) signaling, raised leukotriene B4 levels (recruiting innate inflammatory cells), massive tissue infiltrates of neutrophils, macrophages and dendritic cells (DCs) with a few mast cells and natural killer (NK) cells along with their proinflammatory cytokines (tumor necrosis factor (TNF)-α), all potentiate HS pathophysiology.[13] Various pathways focussing on the crosstalk between DC and NK cells, DC maturation, and communication between innate and adaptive immune cells have been found to be severely affected in HS, further exacerbating the systemic inflammatory response.[13] The role of TNF-α in the inflammatory loop of HS is indicated by the Food and Drug Administration (FDA) approval for the anti-TNF agent adalimumab for the treatment of HS. TNF-α activates endothelial cells of local blood vessels and keratinocytes and augments expression of various lymphocyte-attracting (CXCL11, CCL20) as well as neutrophil-attracting (CXCL1, CXCL2, CXCL8) chemokines, facilitating recruitment of various innate and adaptive immune cells into lesional skin further exaggerating inflammation and tissue damage.[14]

HS has been recently designated as a “systemic neutrophilic dermatosis”; still, this disease is not included in this histopathological spectrum. Significantly upregulated neutrophil-rich serum signature comprising of cathepsin D, IL-17A, C-X-C motif ligand 1 (CXCL1) and lipocalin-2 and severe dermal inflammation with prominent neutrophilic infiltration are the hallmarks of this disease.[12] Irrespective of the precise trigger that initiates the disease process, it is beyond any reasonable doubt that infiltration of HS lesional skin by neutrophils is the end result of the pathophysiological process leading to suppuration and tunnel formation.[15] They do so by releasing various granular proteins including myeloperoxidase, lysozymes, neutrophilic elastases, pentraxins, collagenases, and MMPs as well as by generating NETs (that cause externalization of autoantigens) resulting in extensive tissue destruction. The contribution of neutrophils (an innate immune cellular sensor) in adaptive immunity remains largely underappreciated. Understanding the extent of neutrophilic contribution to the magnitude and quality of adaptive immunity via antigen presentation would help decipher their exact role in HS pathobiology, paving the path for the development of novel therapeutics via manipulating or targeting neutrophils.

Adaptive immunity

Th17 and Th1 (important pillars of cell-mediated immunity) and associated cytokines like INF-γ, IL-17, IL-23, and IL-26 are equally important contenders. Significant Th1/Th17 enrichment and dysregulated Th17/T regulatory cell ratio have been observed in HS skin lesions.[16] IL-17 secreted by Th17 cells stimulates the production of several cytokines (including granulocyte colony-stimulating factor and IL-19) and chemokines (CXCL1 and CXCL8) responsible for massive neutrophil trafficking.[17]

Dysregulated cutaneous and systemic humoral immune response as evidenced by elevated serum total immunoglobulin levels, aggregates of CD138+ plasma cells and CD19+ B-cells in lesional skin, activated B-cell signatures, and antibodies recognizing self-circulating/tissue-citrullinated proteins (e.g., citrullinated peptides in neutrophil extracellular traps, NETs) evidences a role for autoimmunity in HS.[18] These auto-antibodies generate immune complexes that lead to macrophage-activated self-amplifying inflammatory loops crosslinking innate and adaptive immunity [Table 1].[19]

Table 1.

Pathogenetic factors in hidradenitis suppurativa: An overview

Risk factors
• Genetics γ-secretase gene mutations (NCSTN, PSENEN, PSEN1, PSEN2, APH1A/APH1B)
• Life style factors: Obesity (high-fat diet, high BMI, hyper-homocysteinemia, metabolic syndrome, dysbiosis), tobacco smoking
• Sex hormone: Androgens
• Cutaneous microbiome: Porphyromonas & Prevotella
• Signalling pathways: NOTCH, Bruton’s tyrosine kinase (BTK), Spleen tyrosine kinase (SYK)
Cytokines
• IL-1 family cytokines: IL1., IL-18, IL-33, IL-36., IL-36., IL-36., IL-1Ra, IL-36Ra, IL-38, IL-37
• Tumour necrosis factor-α
• Interferons-γ
• IL-17 cytokine family: IL-17A, IL-17C, IL-17E, IL-17F
• IL-12 cytokine family: IL-12, IL-23
• IL-10 cytokine family: IL-10, IL-20, IL-22, IL-26
• IL-6
• Lipocalin 2
• Granulocyte-colony stimulating factor (G-CSF)
Main cell types Non- immune cells  • Keratinocytes  • Fibroblasts Immune cells ➢ Innate  • Neutrophils  • Macrophages  • Dendritic cells ➢ Adaptive  • T-cells: Th1 & Th17 cells  • B-cells & plasma cells	Matrix metalloproteinases (MMPs)  • MMP 1  • MMP 3  • MMP9  • MMP 10	Complement proteins  • C5a  • C5b-9
	Chemokines  • Neutrophil chemokines: CXCL1, CXCL2, CXCL6, CXCL8 (IL-8)  • T-cell chemokines: CXCL9, CXCL10, CXCL11, CCL20,  • B-cell chemokines: BAFF (TNFSF13B), BCA-1/CXCL13, CXCL9, CCL20, IL-16
Serum and skin autoantibodies targeting multiple antigens (broad auto-antigen reactivity)
• Against nuclear antigens: Histones, (H1, H4, H3, H2B, H2A), citrullinated histones (total, H3), dsDNA, ssDNA, nucleosome, nucleolin, chromatin, PCNA, high mobility group box protein 1,
Ro (SS-A), La (SS-B), Sm, U1 RNP, topoisomerase I, PM-Scl75, PL-12, PL-7, fibrillarin, MDA5,
TIF1_, Mi-2., Ku, SRP
• Against cytoplasmic antigens: Protein arginine deiminases (PAD1, PAD2, PAD3), Jo-1, ferritin,
BPI, LAMP2, Hsp70, cardiolipin, .2-microglobulin, ITGB4, proteoglycans, thyroid peroxidase, glutamate decarboxylase 1, annexin A2
• Against extracellular components: Vimentin, filaggrin, collagen (IV, II, III, VI, V, I) cytokeratin 19, fibronectin, vitronectin, myosin, laminin, fibrinogen, citrullinated fibrinogen, apolipoprotein E
• Antibody against neutrophil granule proteins: LL37, azurocidin, myeloperoxidase, proteinase 3, cathepsin G, protein arginine deiminases, metabolic enzymes (enolase, catalase, elastase), lactoferrin, MMP 9
• Against membrane antigens: EGFRs, CTLA4, PD1, PDL1, muscarinic receptors
• Against cytokines: IL-17A, IL-1. TNF-., IL-1., IL-2, IL-12 p70, IL-8, IFN-_, IFN-.2
• Against chemokines: CXCL10, CCL3. CCL2, CCL11
• Anti-Saccharomyces cerevisiae antibodies (ASCA)

Non-immunological cellular players

Non-immune cells including keratinocytes, endothelial cells, and fibroblasts also play an implicit role in HS. Keratinocytes by secreting a variety of pro-inflammatory cytokines including IL-3, IL-19, IL-17C, and IL-36; endothelial cells by expressing a variety of inflammatory ligands; and fibroblasts by producing a variety of matrix metalloproteinases (MMPs) and abnormally inducing kynurenine-tryptophan catabolic pathways, aggravate the pathological process. An imbalance of IL-36 proinflammatory cytokines and decreased levels of its antagonist receptor IL-36Ra further augments hyperkeratosis and lesional inflammation.[19,20] MMPs (involved in the thinning of the basement membrane surrounding the hair follicle unit) induce massive tissue destruction as seen in clinically severe diseases.[15,21,22]

Large, long-term longitudinal studies with follow-ups and employing hypothesis-free integrated omics-based platforms including next-generation sequencing technologies, single-cell transcriptomics, metagenomics, spatial transcriptomics, metabolomics, and proteomics may help in unraveling the intricate and heterogeneous complexities associated with this pathology of the pilosebaceous unit.

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Conflicts of interest

There are no conflicts of interest.